$2.6 million NIH grant backs search for genetic cure in deadly heart disease

(Press-News.org) Fourteen million people worldwide suffer from enlarged hearts, or hypertrophic cardiomyopathy (HCM), a genetic disease that thickens the heart’s walls, making it harder for the organ to pump blood — but many of them don’t know it.

The disease is often undiagnosed, despite being the most common genetic heart disease and having contributed to the sudden deaths of numerous high-profile athletes, including players in the NFL, NBA and NHL.

Now, Sherry Gao, Presidential Penn Compact Associate Professor in Chemical and Biomolecular Engineering (CBE) and in Bioengineering (BE) within Penn Engineering, and Zheng Sun, Associate Professor in Endocrinology, Diabetes and Metabolism within Baylor College of Medicine, have received $2.6 million from the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) to develop new gene editing tools that could address one of the underlying mutations that causes HCM.

“Many cases of HCM can be traced to mutations in a single gene,” says Gao. “We can imagine a future where a single gene-editing treatment cures those cases.”

The Danger of Off-Targets

One of the greatest challenges with gene editing is so-called “off-targets,” when gene editors modify sections of DNA or RNA they should never have touched.

Despite advances in gene editing, including the Nobel Prize-winning CRISPR, off-targets are still common. “If you want to correct a single mutation in 3 billion letters of DNA, you are correcting one letter,” says Sun. “You need tremendous accuracy.”

“Gene-editing systems have the potential to revolutionize medicine by curing previously untreatable diseases”, adds Tyler Daniel, a doctoral student in Gao’s research group, who will be developing the project, “but only if they precisely edit their intended target.”

A Safer Method for Gene Editing

In 2023, Gao’s lab developed a split adenine base editor (sABE), a new type of gene editor that uses a special mechanism to reduce the likelihood of off-target mutations. “We split the editor into two proteins that only work when joined by a small molecule,” says Gao. “It's like a switch — when you don't have the small molecule, there's no gene-editing activity.”

With the new funding, Gao and her collaborators will expand that tool’s capabilities so that it can exchange a wider variety of letters in the genetic code. “Our first version could just swap out an A for a G,” says Gao. “We want to be able to switch C for T, C for G, and so on.”

The team will also test various other small-molecule candidates to see if any drugs that have already gone through clinical trials and proved safe for human health can activate the tool.

Healing the Heart

While Gao’s lab at Penn focuses on molecular engineering, Sun’s lab at Baylor will test these developed split base editing tools in animal models to determine if they can successfully correct a mutation in myosin-binding protein 3 (MYCBP3).

Mutations in the MYCBP3 protein cause about 4 in 10 cases of familial HCM, a common variant of the disease that affects multiple members of the same family. “The goal is to fine-tune the gene editor so that it can efficiently and safely correct mutations,” says Sun.

In addition to correcting MYCBP3, the group will attempt to modify PCSK9, a gene associated with atherosclerosis and the regulation of blood cholesterol. “If we can knock down that gene,” says Gao, “that could help prevent cardiovascular diseases like stroke.”

Ultimately, the researchers hope the award will yield advances in gene editing by reducing off-targets to improve the safety of such tools and make substantial inroads in treating a common cardiovascular genetic disease.

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